Download Joseph L. Izzo, Jr Answer the Genetic Riddle Aging and Systolic

Aging and Systolic Hypertension: Cluster Patterns and Problem-Solving Strategies to
Answer the Genetic Riddle
Joseph L. Izzo, Jr
Hypertension. 2001;37:1067-1068
doi: 10.1161/01.HYP.37.4.1067
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2001 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://hyper.ahajournals.org/content/37/4/1067
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not the Editorial
Office. Once the online version of the published article for which permission is being requested is located,
click Request Permissions in the middle column of the Web page under Services. Further information about
this process is available in the Permissions and Rights Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/
Downloaded from http://hyper.ahajournals.org/ by guest on March 6, 2014
Editorial Commentary
Aging and Systolic Hypertension
Cluster Patterns and Problem-Solving Strategies to Answer
the Genetic Riddle
Joseph L. Izzo, Jr
I
n this issue of Hypertension, Abraham Aviv1 provides a
hypothetical approach to the deeply intertwined relationship between hypertension and aging in humans. He describes
existing evidence for 3 different hypotheses that might
explain why blood pressure increases with age: the “fetal
origin hypothesis,” which holds that a disorder of intrauterine
growth, such as low birth weight, leads to abnormalities in
later life; the theory of “antagonistic pleiotropy,” which
suggests that there was an evolutionary advantage to the
hypertension phenotype because of natural selection of favorable traits closely linked to hypertension; and the theory of
“telomere dependency,” which holds that accelerated loss of
telomeres (specific TTAGGG base pair sequence repeats at
the terminal ends of mammalian chromosomes) limits cellular repair processes and causes vascular aging, stiff blood
vessels, and systolic hypertension.
See p 1060
To fully appreciate the nature of the problem under discussion, it may be wise to review the clinical impact of aging on
blood pressure. In industrialized societies, there is a very
steady age-related increase in systolic blood pressure,
whereas diastolic pressure increases steadily until the sixth
decade of life and then declines.2 We are finally realizing that
this complex age-related behavior of diastolic pressure significantly clouds the clinical definition of hypertension and
that a clearer picture is possible through a paradigm shift to
systolic blood pressure as the more important end point in
diagnosis, risk stratification, and therapy of hypertension.3
The graphic representation of the complex relationship between aging and blood pressure in humans2 should be
prominently featured on posters on the walls of genetic
laboratories as researchers strive to find genotypes that lead
to essential hypertension. Next to that poster should be a
reminder that many of the “intermediate phenotypes” in
hypertension change with age. From a vascular biology
perspective, a telomere-like hypothesis is attractive because
age-related increases in systolic pressure occur at an earlier
age and are more severe in hypertensive individuals, suggesting an apparent acceleration of normal chronological aging in
hypertensive persons. Whether telomere length or either of
the other 2 alternatives explains the process of accelerated
vascular stiffness in hypertensives is unclear, however, and
much further investigation is required before the concept can
be directly applied to hypertension.
From the perspective of this reviewer, the significance of
the article by Aviv1 is that it underscores the need to consider
aging and blood pressure individually and as interactive
variables that require interpretation in the context of a large
number of other factors that could modify them individually
or combined. As stated by Aviv,1 the implications of these
aging hypotheses “serve to draw a critical distinction between
biological age (aging) and chronological age and thereby
offer an answer to a question that presently matters most in
the field of hypertension: why has it been so difficult to
disentangle the genetic components of essential hypertension
and to identify the variant gene responsible for elevated blood
pressure in a large segment of the human population?”
If it is true that aging, hypertension, and their interaction
must be considered simultaneously in advance of the development of the “ultimate” age-dependent phenotype of systolic hypertension, then how will genetic studies be feasible?
Under these circumstances, any candidate cardiovascular
genetic marker must be simultaneously “linked” to the
intermediate phenotypes present at the time of measurement
and to the risk of developing different phenotypes (eg, stiff
blood vessels or systolic hypertension) in later life. The
daunting problem of solving this riddle can be approached
most rationally and efficiently by taking the clinical perspective first. The hypertension phenotype is probably best
viewed as a constellation or cluster of individual phenotypes.
A reasonable assumption is that the study of these clustered
traits (individual phenotypes) will more useful in the identification of critical elements of the genetic profile of hypertension than would be the study of the individual phenotypes
themselves. With this assumption, it should be possible to
match clinical subpopulations of hypertensives with the
phenotypic clusters they represent. Because of the aging
influence, it will also be necessary to study younger populations who are at risk of developing systolic hypertension.
The opinions expressed in this editorial are not necessarily those of the editor or of the American Heart Association.
From the Millard Fillmore Hospital, Buffalo, NY.
Correspondence to Dr Joseph L. Izzo, Jr, Millard Fillmore Hospital, 3 Gates Circle, Buffalo, NY 14209.
(Hypertension. 2001;37:1067-1068.)
© 2001 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
1067
Downloaded from http://hyper.ahajournals.org/
by guest on March 6, 2014
1068
Hypertension
April 2001
If this approach proves to have value, complex phenotype
clusters may be useful to study first. For example, aging is
associated with a progressive increase in aortic stiffness4 and
pulse pressure,5 of which both occur more commonly in
individuals who inherit the C allele of the angiotensin II type
1 (AT1) receptor.6 However, plasma renin activity decreases
with age,7 whereas obesity and insulin resistance increase
with age. Normotensive offspring of hypertensive parents
have been found to have increased cardiac output, wide pulse
pressures, and microcirculatory derangements, including capillary rarefaction and punctate hemorrhagic lesions that are
indistinguishable from diabetic microaneurysms.8 Capillary
rarefaction and abnormally heterogeneous capillary flow
have been proposed as causes of insulin resistance,9 and
abnormal heterogeneity of renal glomerular perfusion has
been suggested as a cause of inappropriate hyperreninemia.10
ACE inhibitors can partially ameliorate the syndrome of
insulin resistance11 and reduce the impact of renal glomerular
capillary rarefaction (ie, diabetic glomerulosclerosis) on the
progression of end-stage renal disease.12,13 This pattern of
syllogistic observations thus “links” macrovascular and microvascular abnormalities, metabolic abnormalities, and alterations in components of the renin-angiotensin system.
Accordingly, profiling studies should pay particular attention
to the specific genes that represent the associated phenotypes
in populations at risk for the development of systolic
hypertension.
It seems to be an inescapable conclusion that an effort to
understand normal and abnormal cardiovascular aging must
be undertaken in parallel with our attempt to elucidate the
mechanisms of essential hypertension. By keeping our eyes
wide open to the age-related patterns of traits or phenotypes
in identifiable at-risk individuals, we may be able to take
advantage of the pleiotropic nature of the syndrome of
essential hypertension in a way that makes genetic association studies more focused and specific. In this complex
setting, the existence of parallel abnormalities in physiologically related systems actually increases the likelihood that
any genetic associations that are found will have biological
significance. The redundancy of such associations in multiple
tissues and in different clinical subpopulations will further
strengthen the evidence that a particular candidate gene or
gene cluster is important. The fact that intermediate pheno-
types change with age is yet another critical dimension that
must be considered in the design of a strategy to approach the
elusive goal of describing the genotypic basis for essential
hypertension.
References
1. Aviv A. Pulse pressure and human longevity. Hypertension. 2001;37:
1060 –1066.
2. Burt VL, Whelton P, Roccella EJ, Brown C, Cutler JA, Higgins M, Horan
MJ, Labarthe D. Prevalence of hypertension in the US adult population:
results from the Third National Health and Nutrition Examination Survey,
1988 –1991. Hypertension. 1995;25:305–313.
3. Izzo JL Jr, Levy D, Black HR. Clinical advisory statement: importance of
systolic blood pressure in older Americans. Hypertension. 2000;35:
1021–1024.
4. Safar ME. Atherosclerotic hypertension: systolic hypertension and arterial compliance in patients with arteriosclerosis obliterans of the lower
limbs. In: Safar ME, Fouad-Tarazi F, eds. The Heart in Hypertension.
Dordrecht: Kluwer Academic Publishers; 1989:123–133.
5. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure
more important than systolic blood pressure in predicting coronary heart
disease events? Circulation. 1999;100:354 –360.
6. Benetos A, Topouchian J, Ricard S, Gautier S, Bonnardeaux A, Asmar R,
Poirier O, Soubrier F, Safar M, Cambien F. Influence of angiotensin II
type 1 receptor polymorphism on aortic stiffness in never-treated hypertensive patients. Hypertension. 1995;26:44 – 47.
7. Weidmann P, Beretta-Piccoli C, Ziegler WH, Keusch G, Gluck Z, Reubi
FC. Age versus urinary sodium for judging renin, aldosterone, and catecholamine levels: studies in normal subjects and patients with essential
hypertension. Kidney Int. 1978;14:619 – 632.
8. Sullivan JM, Prewitt RL, Josephs JA. Attenuation of the microcirculation
in young patients with high-output borderline hypertension. Hypertension. 1983;5:844 – 851.
9. Lillioja S, Young AA, Cutter CL, Ivy JL, Abbott WGH, Zawadzki JK,
Yki-Jarvinen H, Christin L, Secomb TW, Bogardus C. Skeletal muscle
capillary density and fiber type are possible determinants of in vivo
insulin resistance in man. J Clin Invest. 1987;80:415– 424.
10. Sealey JE, Blumenfeld JD, Bell GM, Pecker MS, Sommers SC, Laragh
JH. On the renal basis for essential hypertension: nephron heterogeneity
with discordant renin secretion and sodium excretion causing a hypertensive vasoconstriction-volume relationship. J Hypertens. 1988;6:
763–777.
11. Swislocki ALM, Hoffman BB, Reaven GM. Insulin resistance, glucose
intolerance and hyperinsulinemia in patients with hypertension. Am J
Hypertens. 1989;2:419 – 423.
12. Zatz R, Dunn BR, Meyer TW, Anderson S, Rennke HG, Brenner BM.
Prevention of diabetic glomerulopathy by pharmacological amelioration
of glomerular capillary hypertension. J Clin Invest. 1986;77:1925–1930.
13. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med.
1993;329:1456 –1462.
KEY WORDS: aging 䡲 hypertension, essential 䡲 telomeres
oxygen species 䡲 menopause 䡲 evolution 䡲 genetics
Downloaded from http://hyper.ahajournals.org/ by guest on March 6, 2014
䡲
reactive